Epidermal Langerhans cells drive mechanical allodynia in painful diabetic neuropathy via CCL2-CCR2 neuroimmune signalling
Aims: To determine whether epidermal Langerhans cells (LC) contribute to neuropathic pain in diabetic peripheral neuropathy and to identify the signalling mechanism driving their interaction with sensory nerve fibres in the skin.
Methods: Using a high-fat diet (HFD) mouse model of painful diabetic neuropathy (PDN), the authors combined transgenic LC ablation, behavioural pain assays, single-cell RNA sequencing of paw epidermis and dorsal root ganglia, multiplexed LC secretome profiling, and local pharmacological CCR2 blockade. Human skin biopsies from 15 PDN patients and 9 healthy controls provided translational context.
Results: LC density increased progressively in male HFD mice, correlating inversely with mechanical threshold. Genetic LC depletion prevented both mechanical allodynia and spontaneous pain in males, but not females, revealing a sex-dependent role. scRNA-seq identified male-specific inflammatory and axonal guidance transcriptional programs in HFD LCs, including upregulation of CCL2, Plxnb2, and Plxna1. Secretome profiling confirmed elevated CCL2 protein release from HFD LCs. Local intraplantar CCR2 antagonism transiently but robustly reversed mechanical allodynia. In human biopsies, LC volume and dendritic complexity correlated positively with diabetes duration, while the ratio of intraepidermal nerve fibre density to LC density was reduced in PDN patients.
Conclusions: Epidermal LCs are active peripheral drivers of neuropathic pain in PDN through a sex-dependent, CCL2-CCR2 chemokine-mediated neuroimmune mechanism, representing an accessible therapeutic target at the skin-nerve interface.
Comments: This paper makes a conceptually important contribution by shifting the focus of PDN pathophysiology away from intrinsic neuronal injury toward a skin-resident immune mechanism. The demonstration that LC ablation alone is sufficient to abolish both evoked and spontaneous pain in male diabetic mice places these cells causally upstream of nociceptor sensitisation, not merely as bystanders of inflammation. The sex-specificity finding deserves particular attention. Female mice develop equivalent metabolic dysfunction and allodynia yet show no LC expansion and no pain benefit from LC depletion. The divergent transcriptional profiles, CCL2 and plexin upregulation in males and ion channel changes in females, suggest that the peripheral neuroimmune architecture of PDN pain is fundamentally sex-dimorphic. This has direct clinical relevance: if LC-CCL2 signalling is predominantly a male mechanism, therapeutic strategies targeting this axis may benefit only a subset of patients.
The CCR2 pharmacology is compelling but the reversal of allodynia is transient, lasting approximately two hours. This raises the question of whether peripheral CCR2 blockade alone can deliver durable analgesia, or whether upstream LC reprogramming is needed. The skin accessibility of LCs makes them an attractive therapeutic target; topical or intradermal immunomodulatory approaches warrant exploration. The human biopsy data are a meaningful translational anchor: LC morphological remodelling correlating with diabetes duration suggests progressive neuroimmune activation in chronic PDN. However, the cohort is small, cross-sectional, and clinically heterogeneous. Whether LC remodelling predicts pain severity or treatment response remains entirely open and is the most pressing translational question this paper raises.
